Lonza Inc.

Markus Banziger

John McGarrity

Thomas Meul

David Laffan

Process for the production of 4-hydroxy-2-oxoyrrolidin-1-yl-acetamide, a cerebrally active pharmaceutical agent. A 4-halo-3-alkoxy-butenoic acid ester is reacted with glycine to new intermediate products of the formula: ##STR1## There is further by acid hydrolysis of the alkoxy group, subsequent hydrogenation, esterification of the carboxyl function and finally conversion to the end product by reaction with ammonia.

Process for the production of 4-hydroxy-2-oxopyrrolidin-1-yl-acetamide

Starting from 5-alkylidene or 5-benzylidenetetramic acid optically-active 4-amino-3-hydroxy-carboxylic acids are produced in the (rel-3R,4R) configuration, especially statine. The synthesis process includes the O-acylation of the tetramic acid to the corresponding 4-acyloxy-3-pyrrolin-2-one, a stereoselective hydrogenation to (rel-4R,5R)-4-acyloxy-5-alkyl or 5-benzylpyrrolidin-2-one and an enantioselective enzymatic hydrolysis of the (4R,5R)-enantiomer to the corresponding 4-hydroxypyrrolidin-2-one. The nonhydrolyzed enantiomer is separated and converted into the target compound with (3S,4S) configuration by hydrolytic cleavage of the lactam ring and the ester function and optionally introduction of an amino protective group. Analogously the (3R,4R)-enantiomer can be obtained from the 4-hydroxypyrrolidin-2-one from the enzymatic hydrolysis. The 4-amino-3-hydroxycarboxylic acids producible according to the invention are the structural elements of enzyme inhibitors.

Process for the production of optically-active

Starting from 5-alkylidene or 5-benzylidenetetramic acid, optically-active 4-amino-3-hydroxy-carboxylic acids are produced in the (rel-3R,4R) configuration, especially statine. The synthesis process includes the O-acylation of the tetramic acid to the corresponding 4-acyloxy-3-pyrrolin-2-one, a stereoselective hydrogenation to (rel-4R,5R)-4-acyloxy-5-alkyl or 5-benzylpyrrolidin-2-one and an enantioselective enzymatic hydrolysis of the (4R,5R)-enantiomer to the corresponding 4-hydroxypyrrolidin-2-one. The nonhydrolyzed enantiomer is separated and converted into the target compound with (3S,4S) configuration by hydrolytic cleavage of the lactam ring and the ester function and optionally introduction of an amino protective group. Analogously the (3R,4R)-enantiomer can be obtained from the 4-hydroxypyrrolidin-2-one from the enzymatic hydrolysis. The 4-amino-3-hydroxycarboxylic acids producible according to the invention are the structural elements of enzyme inhibitors.

(2R,3E)-4-halo-3-buten-2-ols are produced by kinetic resolution of racemates from the corresponding racemates. The racemate is esterified by reaction with a carboxylic acid derivative, preferably with chloroacetyl chloride. Then the (R)-ester is enantioselectively hydrolyzed with a lipase from Pseudomonas fluorescens. The corresponding (2R,3E)-4-halo-3-buten-2-ol also can be obtained from the remaining (S)-ester after separation. The compounds are chiral synthesis structural elements for the production of optically active natural substances.

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Brig-Glis, Switzerland

Markus Banziger